This proposal is being submitted for funding consideration through the R21 mechanism in response to the NIDA/NIMH RFA (DA-03-007). The major purpose of this study is to identify biobehavioral mechanisms relating conduct disorder (CD) and drug use among a sample of high risk adolescent males and females. To this end, a cross-sectional design using structural equation modeling will be used to examine the extent to which physiologic and behavioral indices of deficient emotional reactivity and frontal-limbic dysfunction account for the relationship between conduct symptoms and drug problems. The significance of these variables will be weighed in combination with established environmental risk factors common to both conduct problems and drug use. We will examine a total of 250 adolescent males and females at a juvenile correctional facility. Our ongoing work indicates a broader range of conduct problems and drug involvement in this population relative to youth recruited from other settings. The broad spectrum of antisocial behavior and substance use in this population will allow for a more robust test of mechanisms relating CD symptoms with drug problems. Peripheral expression of emotional reactivity and frontal-limbic function will be assessed using the following three indicators: (1) changes in the stress hormone cortisol, (2) emotion-modulated startle paradigm, and (3) performance on the Bechara Gambling Task, an established objective laboratory task designed to capture the particular kinds of processing governed by frontal-Iimbic regions. We believe that conduct problems, especially those that occur prior to adolescence and to substance use, may be a marker for underlying frontal-limbic dysfunction. This underlying dysfunction may, in part, explain why children with conduct problems are especially prone to later substance use disorders. A finding of frontal-limbic dysfunction associated conduct problems that confers liability for drug misuse would provide insights into common biobehavioral etiologic factors of these disorders and point the way toward improved prevention and treatment efforts.